Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents

• Status: Active, not recruiting
• Trial end date: 2024-01-20
• Target enrollment: 0
• Participant gender: All

Summary

Dolutegravir (DTG) is an HIV drug in the integrase inhibitor drug class. This study will test the safety of and immune response to DTG in HIV-1 infected infants, children, and adolescents.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Dolutegravir; Integrase Inhibitors

Criteria

Inclusion Criteria:

• At least 4 weeks but younger than 18 years of age at study entry

• Confirmed HIV-1 infection defined as positive results from two samples collected at different time points (see protocol for more information)

• Participants must belong to one of the ARV exposure groups below:

• 1) ARV-treatment experienced (not including receipt of ARVs as prophylaxis or for prevention of perinatal transmission)

• Previously took ARVs for treatment, but not currently taking ARVs:

• Must have been off treatment for greater than or equal to 4 weeks prior to screening, OR

• Currently taking ARVs for treatment but failing:

• Must be on an unchanged, failing therapeutic regimen within the 4 to 12 weeks prior to screening (less than or equal to 1 log drop in HIV-1 RNA within the 4 to 12 weeks prior to screening). NOTE: To meet this criterion, two HIV RNA levels are required: one from a date between 4-12 weeks prior to study screening and a second one at study screening. The HIV RNA level at screening must be higher than, equal to, or less than or equal to 1 log lower than the prior HIV RNA level. NOTE: Dose adjustments for growth or formula substitutions (i.e., switching from single agent to fixed dose combination) during this 4 to 12 week period, substitutions of one ARV within the same class for toxicity or tolerability management, or discontinuation of ARVs are permitted between the HIV RNA measurements and screening or enrollment. OR

• For participants less than 2 years of age, initiated ARVs for treatment less than 4 weeks prior to screening.

• 2) ARV treatment naive (no exposure to ARVs for treatment; could have received ARVs for prophylaxis or prevention of perinatal transmission)

• If an infant has received nevirapine (NVP) as prophylaxis to prevent perinatal transmission, he or she must have not received NVP for at least 14 days prior to enrollment into Stage I or II.

• HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening. NOTE: For participants enrolling into cohorts IV, IV-DT, and V-DT, the HIV RNA test performed at screening may be pending at the time of enrollment. If the screening HIV RNA is less than or equal to 1000 c/mL, the participant should discontinue study drug (see the protocol for more information).

• Demonstrated ability or willingness to swallow assigned study medications. NOTE: Film coated tablets MAY NOT be crushed or dissolved. Dispersible tablets MAY NOT be cut and must be used in five milligram intervals.

• Parent or legal guardian able and willing to provide signed informed consent.

• Female participants of reproductive potential, defined as having reached menarche, and who are engaging in sexual activity that could lead to pregnancy, must agree to use two contraceptive methods while on study and for two weeks after stopping study drug.

• Males engaging in sexual activity that could lead to HIV-1 transmission must use a condom.

• Optimized background therapy (OBT):

• Participants who are both greater than or equal to 2 years of age and ARV-treatment experienced (meeting entry criterion) must have available at least one fully active drug for the OBT to enroll. If screening genotype testing is inconclusive, historical genotypes obtained within 1 year of screening will be considered by the Protocol Team for determination of fully active drugs.

• Participants who are greater than or equal to 2 years of age and ARV-treatment naive (meeting entry criterion) can enroll if genotype testing has been obtained with results pending.

• Participants less than 2 years of age (either ARV-treatment experienced or ARV treatment naïve) can enroll if genotype testing has been obtained with results pending.

Exclusion Criteria:

• Presence of any active AIDS-defining opportunistic infection

• At enrollment, participant less than 3.0 kg

• Known Grade 3 or greater of any of the following laboratory toxicities within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine transaminase (ALT), lipase, serum creatinine and total bilirubin. A single repeat within the 30 days is allowed for eligibility determination. NOTE: Grade 3 total bilirubin is allowable, if the participant is on atazanavir (ATV).

• ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE:

Grade 4 total bilirubin is allowable, if the participant is on ATV.

• The following liver toxicities within 30 days prior to study entry: ALT greater than 3x the upper limit of normal (ULN) AND direct bilirubin is greater than 2x ULN

• Any prior history of malignancy, with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin

• Clinical or symptomatic evidence of pancreatitis, as determined by the clinician

• Use of any disallowed medications at time of screening (see the protocol for a complete list of disallowed medications)

• Known history of exposure to integrase inhibitor treatment by the participant or participant's mother prior to delivery/cessation of breastfeeding

• Known resistance to an integrase inhibitor

• Women who are pregnant or breastfeeding.

• Participant is currently participating in or has participated in a study with a compound or device that is not commercially available within 30 days of signing informed consent, unless permission from both Protocol Teams is granted

• Participant is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study to a non-IMPAACT study site

• Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study

• Participant has used, or anticipates using, chronic systemic immunosuppressive agents or systemic interferon (e.g., for treatment of hepatitis C virus [HCV] infection) within 30 days prior to beginning DTG study treatment. Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (less than or equal to 30 days) are permitted. (See protocol for more information on disallowed medications.)

• Any condition that would, in the opinion of the site investigator, place the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol.

• Active tuberculosis (TB) disease and/or requirement for treatment that includes rifampin at the time of the screening visit. However, participants who need rifampin treatment while on DTG will be allowed to continue in P1093 provided the DTG dose is adjusted according to the protocol.